[unreadable] Acute, sustained hypoxia, is a commonly linked with progressive neurodegeneration in CNS insults such as stroke, cardiac arrest, asphyxia and neonatal hypoxia. A better understanding of mechanisms that can promote brain tolerance to hypoxia may lead to novel treatments. Hibernating mammals are known to tolerate imposed hypoxia better than non-hibernators. Hibernating animals also go through profound endogenous systemic hypoxia during transitions from hibernation to arousal states without CNS injury. The long-term goal of this proposal is to elucidate mechanisms that maintain brain tissue oxygen tension (PtO2) and prevent hypoxia-induced neurodegeneration in Arctic ground squirrels (AGS), which are a hibernating species. The investigators have observed dramatic changes in the arterial O2 levels of these squirrels during hibernation and upon arousal from hibernation. Compared to the non-hibernating (or euthermic) squirrels the dissolved arterial oxygen levels are much higher during hibernation but drop precipitously to their lowest values upon arousal from hibernation. The investigators have developed techniques to monitor in vivo brain tissue oxygen levels and propose to understand the physiological determinants of the observed shifts in oxygen homeostasis of the artic ground squirrels. [unreadable] [unreadable] Their first aim seeks to determine whether brain PtO2 varies in parallel with PaO2 during the Arctic squirrel hibernation and arousal states. In addition, this aim will explore whether brain PtO2 levels are better maintained during imposed hypoxia in this hibernating species vs. rats, a non-hibernating species. [unreadable] [unreadable] The second aim addresses the physiological mechanisms that may underlie the hibernation and arousal associated changes in PaO2. This aim will try to determine whether brain tissue oxygen tensions are maintained by mechanisms that either decrease brain oxygen consumption or enhance brain O2 delivery. To explore whether a decrease in brain tissue oxygen demand takes place, the investigators will measure brain O2 levels as well as O2 consumption rates during exposure to hypoxia. To explore mechanisms mediating enhanced brain O2 delivery the investigators will first search for evidence supporting angiogenesis. This evidence is to be construed from measurements of brain vascular endothelial growth factor levels via western blotting. Another enhanced delivery mechanism to be explores is alteration in HbO2 affinity. [unreadable] [unreadable] The third aim will attempt to implicate ketosis as neuroprotective mechanism operating during arousal. This is to be done by simply measuring levels of 13hydroxybutyrate in blood and brain tissues during hibernation and arousal. The overall approach of these studies is to use freely moving unanesthetized adult AGS and a novel preparation to monitor in-vivo real time PtO2 in hibernating animals. [unreadable] [unreadable]